PROJECT SUMMARY Aging is associated with physiological dysfunction and increased risk for developing chronic disease. A primary mechanism mediating physiological dysfunction with advancing age, and one of the hallmarks of aging, is chronic low-grade inflammation, termed ?inflamm-aging?. Thus, as emphasized in NIA PAR-15-190, identifying novel anti-inflammatory therapies that reduce inflamm-aging is a high priority for preventing and treating physiological dysfunction with aging. Recently, co-investigator Dr. Charles Dinarello ? an international leader in translational cytokine biology and medicine ? characterized a novel endogenous anti-inflammatory protein, interleukin-37 (IL-37). IL-37 reduces development of morbidity by strongly suppressing inflammation and adverse immune responses in a wide spectrum of disease models. Our preliminary data suggest that IL-37 has beneficial effects on vascular, metabolic, and physical/motor function with aging. We propose to extend our initial studies in mice and translate our findings to middle-aged/older (MA/O) humans. Specifically, we hypothesize that: (1) IL-37 will suppress inflamm-aging by reducing pro-inflammatory signaling, resulting in enhanced vascular, metabolic and physical/motor function with aging in mice. To test this hypothesis, we will determine if transgenic mice with lifelong human IL-37 expression, as well as wild-type mice treated with recombinant IL-37 in late life, demonstrate enhanced vascular (endothelial function, aortic stiffness), metabolic (insulin/glucose function) and physical/motor (exercise capacity, grip strength, endurance) function compared to their respective control groups (i.e., transgenic: old wild-type mice; recombinant IL-37: vehicle-treated controls). (2) Plasma IL-37 concentrations (positively) and gene variants (negatively or positively) will be related to vascular, metabolic and physical/motor function in young and MA/O healthy humans. We will relate circulating IL-37 levels and single nucleotide polymorphisms (SNPs) in the IL-37 gene to the same vascular, metabolic, physical/motor functions described in (1), but in healthy young and MA/O humans. IL-37 will be measured in stored plasma samples from a laboratory database in which >300 subjects have already been phenotyped. The proposed research will be the first of its kind to investigate the effects of the endogenous anti- inflammatory mediator IL-37 on multiple domains of clinically relevant physiological function with aging in both mice and humans. The results of these studies will provide initial evidence for both the mechanistic role and therapeutic potential of IL-37 to maintain/enhance function with human aging.